Animal models are proven investigative tools for study of complex human diseases such as Alzheimer s Disease (AD) and atherosclerosis. Trangenic and bigenic mouse models for presenilin-1 (PS1) and amyloid precursor protein (APP) human gene variants have been instrumental in delineating their roles in AD pathogenesis. However, to date these mouse models have not exhibited key AD pathology such as neurofibrillary tangles, neuronal loss and AD-associated cognitive/neurobehavioral deficits. We hypothesize that a more phenotypically robust and experimentally accessible model of Alzheimer s disease will be obtained in the rat based on key observations: a) rat ApoE is more homologous to human ApoE4 compared with mouse; b) rat complement, like the human has greater levels compared with the mouse and might be a key determinant to the development of neurofibrillary tangles; c) neurobehavioral studies assessing aging and hippocampal-specific learning and memory deficits have been validated in the rat; d) the size of the rat allows lesioning and imaging studies; f) the more robust atherosclerotic phenotype in transgenic rats compared with mice given the same human cholesteryl ester transfer (hCETP) transgene indicates valid modeling for complex diseases. This proposal focuses on the following specific aims. (1) Develop three key inbred Fischer 344 rat AD models with the highest probability for a robust AD phenotype: a) homozygous high-expresser of mutant human APPSWE AD gene, TgAPP, b) homozygous bigenic with both mutant human PSIM146L and hAPPSWE, 2TG[PS1xAPP], and a trigenic rat model, 3Tg]PS1 x APAP x hCETP], which imposes, if not test, hypercholesterolemia-induced exacerbaytion of amyloidogenic APP processing in vivo. (2) Investigate the degree of cognitive deficits in the combinational transgenic rat AD models by measuring hippocampal-dependent working memory and spatial learning and memory at 12, 18, 24 months. 3) Correlate observed hippocampal-dependent neurobehavioral alterations with AD- associated neuropathological alterations at 12, 18, and 24 months. (4) Correlate key neurobehavioral and neuropathological alterations with molecular and cellular markers of AD pathogenesis at 12, 18, and 24 months. Comparative analysis of the proposed rat models will not only address an accessible AD model for mechanistic dissection and therapy development, but also provide insight into the role of complement- and hypercholesterolemia-mediated disease paradigms in AD pathogenesis.